Nature Chemical Biology Contents: April 2013 Volume 9 Number 4, pp 193 - 283

TABLE OF CONTENTS April 2013 Volume 9, Issue 4 Focus Editorial Commentaries Research Highlights News and Views Perspective Review Brief Communications Articles Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement Submit to Nature Chemical Biology The editorial team welcomes contributions from academic, industrial and government sectors across all areas of chemical biology. To submit your next paper to Nature Chemical Biology visit the electronic submission website at: http://mts-nchemb.nature.com/cgi-bin/main.plex   Focus Top Targets In this issue, we present a collection of articles that tackle the challenges in the discovery and validation of new targets for clinical purposes, the application of chemical probes to understand the relationship between targets and biology and the expanding assortment of chemical tools and techniques that can be used to perturb targets that have been considered chemically intractable. Targets Editorial Top Stay on target   p193 doi:10.1038/nchembio.1226 Applying a rigorous chemical biology approach to the selection and validation of clinical targets will increase the success of drug discovery initiatives. Commentaries Top Target validation using chemical probes   pp195 - 199 Mark E Bunnage, Eugene L Piatnitski Chekler and Lyn H Jones doi:10.1038/nchembio.1197 Fully profiled chemical probes are essential to support the unbiased interpretation of biological experiments necessary for rigorous preclinical target validation. We believe that by developing a 'chemical probe tool kit', and a framework for its use, chemical biology can have a more central role in identifying targets of potential relevance to disease, avoiding many of the biases that complicate target validation as practiced currently. Determining target engagement in living systems   pp200 - 205 Gabriel M Simon, Micah J Niphakis and Benjamin F Cravatt doi:10.1038/nchembio.1211 Chemical probes are critical tools for elucidating the biological functions of proteins and can lead to new medicines for treating disease. The pharmacological validation of protein function requires verification that chemical probes engage their intended targets in vivo. Here we discuss technologies, both established and emergent, for measuring target engagement in living systems and propose that determining this parameter should become standard practice for chemical probe and drug discovery programs. The why and how of phenotypic small-molecule screens   pp206 - 209 Ulrike S Eggert doi:10.1038/nchembio.1206 Small-molecule phenotypic screening has high potential in the discovery of new chemical probes and new biological small-molecule targets. This commentary will discuss the basic principles underlying the design of phenotypic screens and propose some guidelines to facilitate the discovery of small molecules from phenotypic screens. Translational synthetic chemistry   pp210 - 213 Sarathy Kesavan and Lisa A Marcaurelle doi:10.1038/nchembio.1207 Providing chemical matter to modulate newly identified biological targets[mdash]as well as pre-existing but chemically intractable ones[mdash]remains a challenge in the discovery of therapeutics. Here, we discuss opportunities for synthetic chemists to make a direct impact in addressing targets that are considered 'undruggable'. Research Highlights Top Neuroscience: Tracing glutamate | Heterocycles: Stitching in selenium | Transcriptional regulation: Find that factor | Pluripotency: Tet à tet | Metabolism: RNA talks back | Drug discovery: Hits for Tat | Biosynthesis: Served with a twist | Plant signaling: Flowers from a sweetheart News and Views Top Structural biology: Protein self-assembly intermediates   pp216 - 217 Michele Vendruscolo and Christopher M Dobson doi:10.1038/nchembio.1210 Proteins can self-assemble into functional states, or they can end up as aberrant and sometimes toxic aggregates. Metastable intermediate states are often detected in these processes, and their structural characterization provides vital information about the balance between functional and pathological behavior in living systems. See also: Article by Jaremko et al. Signaling: Making a leaner Hedgehog   pp217 - 218 Chih-wei Fan, Rubina Tuladhar and Lawrence Lum doi:10.1038/nchembio.1209 Secreted Hedgehog (Hh) proteins are essential in development, and their aberrant activity contributes to certain cancers. Chemically targeting a lipid modification of Hh proteins results in loss of their cellular activity, revealing new strategies for cancer intervention and elucidation of the role of lipids in signal transduction. See also: Brief Communication by Petrova et al. Optopharmacology: A light switch for pain   pp219 - 220 Otto Fajardo and Rainer W Friedrich doi:10.1038/nchembio.1203 A small molecule called optovin acts as a light-sensitive ligand for an ion channel involved in the detection of painful sensory stimuli. This unexpected finding emerged from a behavioral screen in zebrafish and provides a tool for the remote control of pain by light. See also: Article by Kokel et al. Metalloenzymes: Put a ring on it   pp220 - 221 Amy C Rosenzweig doi:10.1038/nchembio.1208 The structure of a bacterial methane oxidation complex reveals how protein-protein interactions can mediate coupling of proton, electron and substrate delivery to a metal active site. Chemical Biology JOBS of the week Postdoctoral Fellowship - Chemical Biology Division New England Biolabs, Inc. MRes in Chemical Biology of Health & Disease Imperial College London Postdoctoral Position in Chemical Biology - Tisch Cancer Institute Mount Sinai School of Medicine (Dar Lab) Postdoctoral Fellow Western University, Ontario, Canada Biostatistician / Computational Biologist Lieber Institute for Brain Development More Science jobs from Perspective Top Systems-level antimicrobial drug and drug synergy discovery   pp222 - 231 Terry Roemer and Charles Boone doi:10.1038/nchembio.1205 Review Top Target identification and mechanism of action in chemical biology and drug discovery   pp232 - 240 Monica Schenone, Vlado Dančík, Bridget K Wagner and Paul A Clemons doi:10.1038/nchembio.1199 Brief Communications Top Gold biomineralization by a metallophore from a gold-associated microbe   pp241 - 243 Chad W Johnston, Morgan A Wyatt, Xiang Li, Ashraf Ibrahim, Jeremiah Shuster, Gordon Southam and Nathan A Magarvey doi:10.1038/nchembio.1179 Bacteria find creative solutions to occupy a variety of environmental niches. A peptide isolated from a gold-associated microbe provides a new example of this adaptation, binding gold and precipitating it to protect the organism from metal toxicity. Chemical compounds Coordination of auxin and ethylene biosynthesis by the aminotransferase VAS1    pp244 - 246 Zuyu Zheng, Yongxia Guo, Ondřej Novák, Xinhua Dai, Yunde Zhao, Karin Ljung, Joseph P Noel and Joanne Chory doi:10.1038/nchembio.1178 The VAS1 aminotransferase regulates the shade avoidance response in Arabidopsis thaliana by shunting metabolic flux away from auxin and ethylene, two growth regulatory plant hormones. Inhibitors of Hedgehog acyltransferase block Sonic Hedgehog signaling   pp247 - 249 Elissaveta Petrova, Jessica Rios-Esteves, Ouathek Ouerfelli, J Fraser Glickman and Marilyn D Resh doi:10.1038/nchembio.1184 Hedgehog acyltransferase (Hhat) attaches a palmitate to Sonic hedgehog, but the importance of this enzyme has been difficult to discern. RU-SKI 43 is a potent and selective inhibitor of Hhat in vitro and in cells that will allow scientists to investigate the importance of Hhat for Shh signaling. Chemical compounds See also: News and Views by Fan et al. Articles Top Induction of innate and adaptive immunity by delivery of poly dA:dT to dendritic cells   pp250 - 256 Scott Barbuto, Juliana Idoyaga, Miquel Vila-Perelló, Maria P Longhi, Gaëlle Breton, Ralph M Steinman and Tom W Muir doi:10.1038/nchembio.1186 A conjugate generated by expressed protein ligation between an antibody targeting dendritic cells (DCs) and an immune-stimulating double-stranded DNA reveals that DCs can mediate both innate and adaptive immunity and represents its potential utility as a vaccine adjuvant. Photochemical activation of TRPA1 channels in neurons and animals   pp257 - 263 David Kokel, Chung Yan J Cheung, Robert Mills, Jaeda Coutinho-Budd, Liyi Huang, Vincent Setola, Jared Sprague, Shan Jin, Youngnam N Jin, Xi-Ping Huang, Giancarlo Bruni, Clifford J Woolf, Bryan L Roth, Michael R Hamblin, Mark J Zylka, David J Milan and Randall T Peterson doi:10.1038/nchembio.1183 Optovin is a small molecule that renders zebrafish embryos responsive to light through generation of singlet oxygen and activation of the TrpA1b channel, providing a new tool for optogenetics. See also: News and Views by Fajardo & Friedrich Cold denaturation of a protein dimer monitored at atomic resolution   pp264 - 270 Mariusz Jaremko, Łukasz Jaremko, Hai-Young Kim, Min-Kyu Cho, Charles D Schwieters, Karin Giller, Stefan Becker and Markus Zweckstetter doi:10.1038/nchembio.1181 NMR structures of the homodimeric repressor protein CylR2 collected from 25 °C to –16 °C provide glimpses of the molecular changes that occur during cold denaturation, yielding insights into protein folding and oligomerization. See also: News and Views by Vendruscolo & Dobson Allosteric inhibition of hypoxia inducible factor-2 with small molecules   pp271 - 276 Thomas H Scheuermann, Qiming Li, He-Wen Ma, Jason Key, Lei Zhang, Rui Chen, Joseph A Garcia, Jacinth Naidoo, Jamie Longgood, Doug E Frantz, Uttam K Tambar, Kevin H Gardner and Richard K Bruick doi:10.1038/nchembio.1185 A new small-molecule inhibitor that selectively binds an internal cavity in HIF-2α allosterically disrupts HIF-2α–ARNT interaction in vitro and in cells. This compound should allow scientists to interrogate HIF-2α's activity in hypoxia and cancer cells. Chemical compounds Lysine and arginine biosyntheses mediated by a common carrier protein in Sulfolobus    pp277 - 283 Takuya Ouchi, Takeo Tomita, Akira Horie, Ayako Yoshida, Kento Takahashi, Hiromi Nishida, Kerstin Lassak, Hikari Taka, Reiko Mineki, Tsutomu Fujimura, Saori Kosono, Chiharu Nishiyama, Ryoji Masui, Seiki Kuramitsu, Sonja-Verena Albers, Tomohisa Kuzuyama and Makoto Nishiyama doi:10.1038/nchembio.1200 One pathway for lysine biosynthesis uses a carrier protein, LysW, to protect the substrate. LysW is now shown to mediate entry of a second substrate into the same metabolic pathway, with structural and biochemical evidence identifying an amino acid motif that determines substrate specificity. Top Advertisement Subscribe today to Nature Chemical Biology Reflecting the diversity and excitement of chemical biology research. 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